Abstract A consortium of five studies, known as the Preclinical AD Consortium, was established in October 2014 to accelerate understanding of the preclinical phase of AD. While each of these studies has federal funding to support the longitudinal collection of clinical, cognitive, genetic and biomarker data among individuals who were cognitively normal when first enrolled, it is understood that it is essential to combine their data together in order to address some of the most challenging questions related to the evolution of AD during its earliest phases. One of the primary goals of these studies has been to identify individuals at greatest risk for progression in order to facilitate early intervention. However, these studies have also been gathering information relevant to risk and protective factors that may influence vulnerability to disease. These factors are challenging to study because the effect of any one risk factor may be modest and large sample sizes are needed in order to examine potential interactions of effects, particularly as they pertain to biomarkers of disease. This application (in response to PAR-17- 054), provides the unique opportunity to leverage the data prospectively collected by five ongoing studies of preclinical AD in order to examine a range of risk and protective factors that may influence risk for progression from normal cognition to mild cognitive impairment. To accomplish the goals of the grant, we are also proposing additional biomarker assays (in blood and cerebrospinal fluid) and the generation of new genetic data, to address selected issues. The potential risk and protective factors the consortium is proposing to examine include: gender, genetics, cognitive reserve, physical activity, personality, depression and vascular risk factors. The consortium represented by this application, with its' extensive longitudinal clinical and cognitive data, and rich biomarker collection (including blood, CSF, MRI scans and PET scans) offers a unique opportunity to address these important issues.